In 1995, Biswal et al. (a Co-Investigator on this proposal) discovered that low frequency (0.01-0.08Hz) fluctuations in the BOLD signal are correlated across brain regions under resting conditions, a phenomenon referred to as functional connectivity (FC). These fluctuations are easily observable in the absence of a constraining behavioral task, during sleep or anesthesia. Studies of FC have yielded intriguing between-group differences in ADHD, autism, and depression compared to healthy controls. Reduced FC has also been observed in preliminary studies in schizophrenia. Although FC is an area of great interest, its structural basis and functional significance is poorly understood. FC may be mediated by white matter connectivity between the brain regions that form these networks. If so, white matter integrity should correlate with FC. This question is the overarching hypothesis of the current proposal. White matter integrity can be addressed using diffusion tensor imaging (DTI), which quantifies the magnitude and directionality of water diffusion. Fractional anisotropy (FA) is a DTI-derived measure that is maximal in white matter, where highly ordered structure gives rise to directional (anisotropic) diffusion. Interregional brain dysconnectivity has been proposed as a critical underlying basis for the myriad deficits seen in schizophrenia. As such, the disorder represents an interesting test case for our overarching hypothesis. FA deficits are widespread in schizophrenia. In patients, FA correlates with performance in regions known to be involved in sensory and cognitive deficits. We will study 32 patients with schizophrenia and 32 age- and sex-matched healthy controls, as well as 15 family members of patients with SZ, to examine relationships among 1) functional connectivity, 2) white matter integrity, reflected by FA, and 3) neurophysiological, sensory, and neuropsychological function. We will examine FA correlates of occipital, auditory, and limbic FC, as well as the relevance of these networks for visual, auditory, and response inhibition deficits. We predict that resting state FC will be correlated with FA in these subjects. We also predict that reduced FC in occipital, auditory, and limbic regions in schizophrenia will be correlated with poorer sensory and cognitive function. Our hypotheses are supported by our preliminary findings showing FC/FA correlations in limbic and sensory cortices. PUBLIC HEALTH RELEVANCE Schizophrenia a serious disorder that involves sensory and cognitive deficits as well as psychiatric symptoms. The proposed work will examine abnormalities in brain anatomical and functional using MRI. The results will provide us with a better understanding of the neural basis of the disorder.